Neuroplasticity is the ability of the nervous system to respond to intrinsic or extrinsic stimuli by reorganizing its structure, function and connections. Neuroplasticity is one of the most important areas in contemporary neuroscience. It is widely considered to be a cellular mechanism underlying learning and memory (Harnessing neuroplasticity for clinical applications. Cramer, S. C. et al. Brain. 2011; 134(Pt. 6): 1591-609).
Neuroplastic changes have been observed in a large variety of diseases, such as Alzheimer's disease; amyotrophic lateral sclerosis; Angelman syndrome; Asperger syndrome; autistic disorders; bipolar disorder; brain injury; Creutzfeldt-Jakob disease; depression; Down syndrome; epilepsy; fragile X syndrome; Friedrich's ataxia; frontotemporal dementia; frontotemporal lobar degeneration; Huntington's disease; Lewy body disease; multiple sclerosis; multiple system atrophy; Parkinson's disease; Pick's disease; post-traumatic stress disorders; prion disorders; Rett syndrome; schizophrenia; spinal and bulbar muscular atrophy; spinal cord injuries; spinocerebellar ataxias; stroke; supranuclear palsy; progressive and tuberous sclerosis.
The scientific challenge to alleviate human suffering in these diseases is enormous.
Neurodegenerative Diseases
The 21st century is facing an epidemic of neurodegenerative diseases. Alzheimer's disease, Huntington's disease and Parkinson's disease are highly prevalent all over the world and have a high social and economic impact.
The Johns Hopkins Bloomberg School of Public Health has estimated the prevalence of Alzheimer's disease at 26.6 million people worldwide, with an estimated 5.4 million in the U.S. alone. By 2050, these figures are expected to have risen to 106 million and 16 million, respectively (Brookmeyer, R. et al. Alzheimers Dement 2007, 3(3): 186-91; Alzheimers Dement 2011, 7(2): 208-44. Parkinson's disease affects around 0.3% of the population in general, with 1% of those over 60 years of age affected and 4-5% of those over 85 years of age (Rao, S. S. et al. Am Fam Physician 2006, 74(12): 2046-54).
Huntington's disease has a worldwide prevalence of 5.7 per 100,000 inhabitants (Pringsheim, T. et al. Mov Disord 2012, 27(9): 1083-91).
The costs associated with these conditions are very high. In 2010, the overall cost of dementia reached USD 604 billion (World Alzheimer Report 2010: The global economic impact of dementia; Alzheimer's Disease Intemational, 2010) and the cost of Alzheimer's disease is likely to rise to USD 1.1 trillion by 2050 (2011 Alzheimer's disease facts and figures; Alzheimer's Association, March 2011). Similarly, Parkinson's disease is estimated to cause yearly costs of approximately USD 23 million (Huse, D. M. et al. Mov Disord 2005, 20(11): 1449-54).
Given the social and economic impact of neurodegenerative diseases, better, more effective treatments are urgently needed. The Alzheimer's Association argues that were a treatment to be discovered that could delay the onset of the disease by 5 years, the number of patients in the U.S. with dementia would fall by nearly 2 million (Brookmeyer, R. et al. Am J Publ Health 1998, 88(9): 1337-; Coley, N. et al. Epidemiol Rev 2008, 30: 35-66) resulting in a yearly saving in health care costs of USD 50 billion (Mount, C. and Downton, C. Nat Med 2006, 12(7): 780-4).
Pharmacotherapies to increase neuroplasticity through molecular manipulation of different cellular and synaptic pathways are needed, since at present only modest or small benefits have been achieved in the treatment of the above-mentioned diseases.
Thus, there is a need to discover new drugs which are able to promote neuroplasticity in the context of nervous system diseases and developmental, behavioral and mental disorders where cognitive deficits—particularly in learning and memory—are associated with illness.
The role of herbal medicines in the treatment of some of these diseases has become well established, with clinical evidence for phytotherapeutic preparations using plants. We have reviewed different plants and their components as a source of active agents that may serve as leads and scaffolds for the development of efficacious drugs for a multitude of CNS diseases, as well as developmental, behavioral and mental disorders.
Salidroside is one of the most potent compounds in Rhodiola rosea L. It is well known as an adaptogen in tradition Chinese medicine and has been reported to show diverse pharmacological activities, including antioxidant (Prasad, D. et al. Mol Cell Biochem 2005, 275(1-2); 1-6), antiaging (Mao, G.maoX. Biomed. Environ. Sci. 2010, 23(2): 161-6) and anti-fatigue (Darbinyan, V. Phytomedicine 2000, 7(5): 365-71). Many reports and reviews reveal that salidroside exhibits potent neuroprotective activity (Zhang, L. Neurochem Int 2010, 57(5): 547-55; Li, Q. Y. et al. Neurosci Lett 2010, 481(3): 154-8. Yu, S. et al. Cell Mol. Neurobiol. 2008, 28(8): 1067-8). We selected tyrosol, the aglycone of salidroside, as a starting material to design new compounds for the treatment of neurological disorders.
After intense investigations the present inventors found that the compounds of formula (I) have utility as neuroplasticity promoters and are useful in the enhancement of memory consolidation and learning and in CNS diseases and/or mental disorders associated with cognitive deficits. Additionally, the compounds show pleiotropic effects which can be explained mechanistically by their actions on different targets, i.e., binding to receptors and inhibition of enzymes. These effects may allow the use of the compounds in the treatment of a variety of other diseases, including pain and depression. In particular, the compounds of formula (I) have been shown to be highly active in animal models of memory consolidation after acute administration, with long-lasting effects, as well as in models of pain and depression. These characteristics surprisingly differentiate compounds of formula (I) from those described in the literature.
N=10-12 mice per group. Mice had received an acute i.p. injection of saline (WT 1st bar, fmr1 KO 3rd bar) or 30 mg/kg Example 2 (Wild Type 2nd bar, fmr1 KO 4th bar) 24 h before the session. Data are expressed as mean±S.E.M. Two way ANOVA Treatment effect Φ p<0.05, Genotype x Treatment interaction p<0.05, Bonferroni as post hoc ***p<0.001, **p<0.01, *p<0.05.